Absorption Half-life Research Articles

The relationships of plasma profenofos and ethanol concentrations to clinical outcome in acute profenofos self-poisoning

Introduction Many patients acutely self-poisoned with organophosphorus insecticides have co-ingested ethanol. Currently, profenofos 50% emulsifiable concentrate (EC50) is commonly ingested for self-harm in Sri Lanka. Clinical experience suggests that ethanol co-ingestion makes management more difficult. Therefore, we aimed to determine the relationships between plasma ethanol concentration, plasma profenofos concentration and its toxicokinetics, and clinical outcome in acute profenofos self-poisoning. Methods Demographic and clinical data, including a history of ethanol ingestion and blood samples, were prospectively collected from all cases of acute poisoning with profenofos EC50 presenting to Teaching Hospital Peradeniya, Sri Lanka, over four years. Plasma samples were analyzed by gas chromatography–mass spectrometry to quantify the ethanol (n = 99) and profenofos (n = 30 [15 with ethanol, 15 without ethanol]) concentrations. The PKSolver program was used to calculate the toxicokinetic parameters. Results Of 99 patients (male 78/99) with acute profenofos self-poisoning, 50 reported a history of ethanol co-ingestion. Plasma from 44 of 99 profenofos-poisoned patients had detectable ethanol concentrations. No statistical difference was observed between the mortality in the ethanol group and the no ethanol group (5/44 [11.4%] versus 3/55 [5.5%]; P = 0.461). Similarly, the median half-lives of plasma profenofos absorption in the ethanol and no ethanol groups (0.1 h and 0.1 h, respectively; time 0–24 h) were not statistically different (P = 0.6594). However, the median half-life of plasma profenofos elimination was significantly longer in the ethanol group than the no ethanol group (23.1 h and 9.9 h, respectively; time 0–24 h; P = 0.0002). According to the regression analysis, the half-life of plasma profenofos elimination was longer by 29.4 h in the ethanol group (P = 0.013). Discussion No significant differences in outcomes, including death and endotracheal intubation rates, were found between those who did and did not co-ingest ethanol. No differences were found in toxicokinetic variables between the ethanol and no ethanol groups, but the ethanol group had a longer elimination half-life. Conclusion The co-ingestion of ethanol leads to a slowing of the elimination kinetics of profenofos. However, the study did not reveal a significant impact of ethanol co-ingestion on clinical outcomes.

Population pharmacokinetic analysis identifies an absorption process model for mycophenolic acid in patients with renal transplant.

The pharmacokinetics (PKs) of mycophenolic acid (MPA) exhibit considerable complexity and large variability. We developed a population pharmacokinetic (popPK) model to predict the complex PK of MPA by examining an absorption model. Forty-two patients who had undergone renal transplantation were included in this study. popPK analysis, incorporating several absorption models, was performed using the nonlinear mixed-effects modeling program NONMEM. The MPA area under the concentration-time curve at 0-12 h (AUC0-12) was simulated using the final model to calculate the recommended dose. The PK of MPA was adequately described using a two-compartment model incorporating sequential zero- and first-order absorption with lag time. Total body weight, renal function (RF), and posttransplantation day (PTD) were included as covariates affecting MPA PK. The final model estimates were 7.56, 11.6 L/h, 104.0 L, 17.3 L/h, 169.0 L, 0.0453, 0.283, and 1.95 h for apparent nonrenal clearance, apparent renal clearance, apparent central volume of distribution, apparent intercompartmental clearance, apparent peripheral volume of distribution, absorption half-life, lag time, and duration of zero-order absorption, respectively. Simulation results showed that a dose regimen of 500-1000 mg twice daily is recommended during the early posttransplantation period. However, dose reduction could be required with increased PTD and decreased RF. The complex PK of MPA was explained using an absorption model. The developed popPK model can provide useful information regarding individual dosing regimens based on PTD and RF.

Metabolic pathways, pharmacokinetic, and brain neurochemicals effects of capsaicin: Comprehensively insights from in vivo studies

BackgroundCapsaicin (CAP), a prominent component of chili pepper known for its potent agonistic effects on TRPV1, has attracted significant attention for its diverse physiological effects. Nevertheless, there remains a paucity of data concerning its in vivo distribution, metabolism, pharmacodynamic properties, and influence on the metabolic profile of the brain. MethodsStable isotope tracing, in vitro enzyme incubation, microdialysis coupled with UHPLC-MS/MS techniques were employed to investigate the in vivo metabolic pathways, distribution, and pharmacokinetic properties of CAP, and the potential biases in metabolic pathways was elucidate through molecular docking. Furthermore, the effect of CAP on brain metabolic profiles was assessed using untargeted metabolomics, and spatial visualization analysis was conducted through mass spectrometry imaging. ResultsCAP was distributed predominantly in the kidneys, with lower content in the liver, heart, lungs, brain, and spleen following peripheral administration, and the absorption half-life in the body was about 20 min. CAP primarily underwent alkyl terminal dehydrogenation, hydroxylation, and macrocyclization metabolic pathways under the action of CYP2C9, CYP2C19 and CYP2D6, resulting in at least four metabolites. Among them, the hydroxylation products were main metabolites and the dehydrogenation product 16,17-dihydrocapsaicin could interact with the key binding sites Leu515 and Thr550 of TRPV1 like CAP. CAP quickly diffused to various brain regions and the metabolic characteristics in the striatum were relatively different from that in the blood. The distribution of CAP in the brain primarily triggered the release of neurotransmitters in areas associated with reward, cognition, and memory. Both acute and chronic exposure to CAP elevated amino acid levels in cortical regions, while producing contrasting effects on nucleotide metabolites. ConclusionThis study offers an initial in-depth analysis of the distribution patterns, metabolic pathways and pharmacodynamic properties of CAP in the body and brain. These findings established a basis for further studies on CAP's pharmacology properties and its influence on the central nervous system.

Development of an In-situ Nasal Gel Formulation of Bepotastine Besilate for the Treatment of Allergic Rhinitis

The objective of this research was to formulate and evaluate mucoadhesive in situ nasal gels as a novel delivery system for Bepotastine Besilate. Aiming to provide sustained drug release directly at the site of action, thereby reducing the need for frequent dosing due to the drug's rapid absorption and short half-life. A series of eight formulations were developed using varying ratios of Poloxamer 407 and Poloxamer 188. The formulations exhibited a visually clear sol phase, indicating uniform dispersion of ingredients, with gelling temperatures ranging from 33.3±0.41 to 36.7±0.73°C. The gelling time, an important parameter for user convenience and efficacy, ranged from 15.7±01.52 to 43.3±20.80 s, meeting practical application requirements. Furthermore, all formulations consistently achieved a drug content of over 95%, ensuring dosage uniformity and efficacy. The pH values of the formulations were within the acceptable range of 6.13±0.10 to 6.91±0.02, minimizing the risk of mucosal irritation upon application. Importantly, the mucoadhesive strength ranged from 1056±0.32 to 6456± 045 dyne/cm², indicating robust adhesion to nasal mucosa, which is critical for prolonged drug retention and sustained release. In vitro drug release studies demonstrated sustained release profiles exceeding 4 hours for all formulations, following Higuchi kinetics, suggesting controlled drug release from the gel matrix. Accelerated stability studies corroborated the formulations' stability over the test period, indicating their potential for long-term storage and commercial viability. Additionally, FTIR analysis revealed no evidence of drug-polymer interactions, confirming the compatibility of Bepotastine Besilate with the selected polymer matrix. These comprehensive findings support the potential of in situ nasal gels as an effective and promising strategy for enhancing the therapeutic efficacy of Bepotastine Besilate, thereby improving patient outcomes.

Doxycycline pharmacokinetics and tissue depletion in striped catfish (Pagasianodon hypophthalmus) after oral administration.

The pharmacokinetics and residue depletion of doxycycline (DOX) in striped catfish (Pagasianodon hypophthalmus) after oral dosage were investigated. The pharmacokinetic experiment was conducted in an aquarium, while the experiment of residue depletion was performed in both an aquarium and earth ponds. Medicated feed was administered orally using the gavage method at a dosage of 20 mg/kg body weight. Blood, liver, and kidney from medicated fish samples were collected. In the depletion experiments, fish were fed medicated feed for five consecutive days at a dosage of 20 mg/kg body weight, with samples collected during and after medication. The concentrations of DOX were quantified using an LC-MS/MS system. The pharmacokinetics parameters of DOX in striped catfish included the absorption rate constant (ka), absorption half-life (T1/2abs), maximal plasma concentration (Cmax), time to maximal plasma concentration (Tmax), and area under the plasma concentration-time curve from time 0 to 96 h (AUC0-96 h) which were 0.12 h-1, 5.68 h, 1123.45 ng/mL, 8.19 h, and 25,018 ng/mL/h, respectively. Residue depletion results indicated that the withdrawal times of DOX in muscle (with skin) from fish kept in the aquarium were slightly longer than that in fish raised in earth ponds, corresponding to 194 degree-days compared with 150 degree-days. In conclusion, administration of DOX at the dosage of 20 mg/kg body weight can be used for treatment of bacterial infections in striped catfish, and a withdrawal time of 5 days at 29.4°C will ensure consumer food safety due to the rapid depletion of DOX from muscle and skin.

Penciclovir pharmacokinetics after oral and rectal administration of famciclovir in African elephants (Loxodonta africana) shows that effective concentrations can be achieved from rectal administration, despite lower absorption.

To evaluate the pharmacokinetics of famciclovir and its metabolite penciclovir following a single dose administered orally and rectally in African elephants (Loxodonta africana). 15 African elephants (6 males and 9 females) of various ages. Famciclovir (15 mg/kg) was administered orally or per rectum once, with at least a three-week washout period between administrations. Blood was collected at 13 different timepoints per administration for 6 elephants, occurring between February and March 2020. An additional 9 elephants were sampled at variable timepoints per administration utilizing a sparse sampling design between July 2020 and January 2021. Plasma famciclovir and penciclovir levels were measured via HPLC and fluorescence detection. Pharmacokinetic analysis was completed in the summer of 2021 using noncompartmental analysis and nonlinear mixed-effects modeling. Famciclovir was not detected in any sample, suggesting complete metabolism. Key pharmacokinetic parameters for penciclovir following oral administration were time to maximum concentration (tmax; 2.12 hours), area under the concentration-versus-time curve (AUC; 33.93 μg·h/mL), maximum observed concentration (Cmax; 3.73 μg/mL), and absorption half-life (t1/2; 0.65 hours). Following rectal administration, the values were: tmax, 0.65 hours; AUC, 15.62 μg·h/mL; Cmax, 2.52 μg/mL; and absorption t1/2, 0.13 hours. Famciclovir was rapidly metabolized to penciclovir. Oral administration resulted in slower absorption but higher maximum plasma concentration and higher AUC compared to rectal administration. African elephants administered famciclovir via oral and rectal routes resulted in measurable serum penciclovir, and these findings may be utilized by clinicians treating viral infections in this species.

Comprehensive ocular and systemic pharmacokinetics of dexamethasone after subconjunctival and intravenous injections in rabbits

Even though subconjunctival injections are used in clinics, their quantitative pharmacokinetics has not been studied systematically. For this purpose, we evaluated the ocular and plasma pharmacokinetics of subconjunctival dexamethasone in rabbits. Intravenous injection was also given to enable a better understanding of the systemic pharmacokinetics. Dexamethasone concentrations in plasma (after subconjunctival and intravenous injections) and four ocular tissues (iris-ciliary body, aqueous humour, neural retina and vitreous) were analysed using LC-MS/MS.Population pharmacokinetic modelling for plasma data from both injection routes were used, and for first time the constant rate of absorption of dexamethasone from the subconjunctival space into plasma was estimated (ka,plasma = 0.043 min−1, i.e. absorption half-life of 17.3 min). Non-compartmental analysis was used for the ocular data analysis and resulting in ocular drug exposure of iris-ciliary body (AUC0-∞= 41984 min·ng/g) > neural retina (AUC0-∞= 25511 min·ng/g) > vitreous (AUC0-∞= 7319 min·ng/mL) > aqueous humour (AUC0-∞= 6146 min·ng/mL). The absolute bioavailability values after subconjunctival injection, reported for the first time, were 0.74 % in aqueous humour (comparable to topical dexamethasone suspensions), and 0.30 % in vitreous humour (estimated to be higher than in topical administration).These novel and comprehensive pharmacokinetic data provide valuable information on the potential for exploiting this route in ocular drug development for treating both, anterior and posterior segment ocular diseases. Moreover, the new generated dexamethasone-parameters are a step-forward in building predictive pharmacokinetic models to support the design of new subconjunctival dexamethasone formulations, which may sustain drug effect for longer period of time.

New Oral PCSK9 Inhibitor: "MK-0616".

MK-0616, a novel oral macrocyclic peptide inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9), represents a significant advancement in the treatment of hypercholesterolemia. Unlike current PCSK9 inhibitors, which are injectable monoclonal antibodies and siRNA molecules, MK-0616 offers a patient-friendly alternative. The development of MK-0616 involved innovative synthetic chemistry and in vitro mRNA display technology. This cutting-edge approach led to the creation of an orally administered peptide with the ability to cover a larger portion of PCSK9 compared to smaller, linear peptides. Phase 1 and 2b clinical trials have demonstrated MK-0616's safety, efficacy, and pharmacokinetics. These trials indicate the drug's dose-dependent systemic absorption and long half-life. Notably, MK-0616 has exhibited comparable low-density lipoprotein cholesterol-lowering effects to currently available PCSK9 inhibitors, all while maintaining good tolerability in diverse patient populations, including those concurrently on statin therapy. As MK-0616 advances to Phase 3 trials, its lipid-lowering potential for heterozygous familial hypercholesterolemia and its impact on reducing the time to adverse cardiac events will be evaluated in a broad and diverse population, including underrepresented groups. The results achieved so far are promising for individuals with hypercholesterolemia, as they offer a potential solution for effectively lowering low-density lipoprotein cholesterol in patients on statin therapy and mitigating the risk of cardiovascular events. Ongoing research and monitoring will be critical to establish its long-term safety and efficacy, but MK-0616 may emerge as a valuable addition to the array of lipid-lowering therapies available to patients.

Endotoxin-Induced Sepsis on Ceftriaxone-Treated Rats' Ventilatory Mechanics and Pharmacokinetics.

Sepsis can trigger acute respiratory distress syndrome (ARDS), which can lead to a series of physiological changes, modifying the effectiveness of therapy and culminating in death. For all experiments, male Wistar rats (200-250 g) were split into the following groups: control and sepsis-induced by endotoxin lipopolysaccharide (LPS); the control group received only intraperitoneal saline or saline + CEF while the treated groups received ceftriaxone (CEF) (100 mg/kg) IP; previously or not with sepsis induction by LPS (1 mg/kg) IP. We evaluated respiratory mechanics, and alveolar bronchial lavage was collected for nitrite and vascular endothelial growth factor (VEGF) quantification and cell evaluation. For pharmacokinetic evaluation, two groups received ceftriaxone, one already exposed to LPS. Respiratory mechanics shows a decrease in total airway resistance, dissipation of viscous energy, and elastance of lung tissues in all sepsis-induced groups compared to the control group. VEGF and NOx values were higher in sepsis animals compared to the control group, and ceftriaxone was able to reduce both parameters. The pharmacokinetic parameters for ceftriaxone, such as bioavailability, absorption, and terminal half-life, were smaller in the sepsis-induced group than in the control group since clearance was higher in septic animals. Despite the pharmacokinetic changes, ceftriaxone showed a reduction in resistance in the airways. In addition, CEF lowers nitrite levels in the lungs and acts on their adverse effects, reflecting pharmacological therapy of the disease.

Promise: Investigation into the Combination of a Potent Beti with Ruxolitinib in Patients with High or Intermediate-2 Risk Myelofibrosis Not Receiving an Adequate Response with Ruxolitinib Alone

ISRCTN: 12451433 Background: Myelofibrosis (MF), a chronic myeloproliferative neoplasm (MPN), often results in progressive splenomegaly and cytopenia (1). Acute myeloid leukaemia develops in 10-20% of patients, and median survival with intermediate-2 disease is four years (2). Stem cell transplant can be curative, but is only suitable for younger, comorbidity-free patients (median MF diagnosis is 73.6 years) (3). Janus Kinase 2 (JAK2) mutation is common in MPN, and the JAK1/2 inhibitor ruxolitinib was approved in 2011 (4). However, patients still experience high disease burden, with a clear need for further treatments. Research has now focused on bromodomain and extra terminal (BET) inhibitors (5), in particular the role these have in disease associated inflammation (6). Preclinical data suggests BETi disrupts this inflammation leading to anti-fibrotic activity within MPN models. BETi with ruxolitinib eliminates fibrosis in MF mouse models thus overcoming a limitation of ruxolitinib monotherapy (7). OPN-2853 (previously PLX2853) is potent against isolated bromodomains from multiple BET proteins with rapid drug absorption, high Cmax, and short half-life differentiating it from other BETi. Preclinical efficacy has been demonstrated across a range of hematologic malignancies. PROMise is evaluating OPN-2853 in combination with ruxolitinib to identify the recommended phase 2 dose (RP2D). Methods: Primary Objectives: To assess the RP2D of OPN-2853 in combination with ruxolitinib that is safe and tolerableTo assess the efficacy of the combination of OPN-2853 and ruxolitinib for reduction in spleen size PROMise is a single country (UK) multicentre study, recruiting up to 60 patients with high or intermediate-2 risk MF who are not receiving an adequate response on ruxolitinib alone. Patients must have been treated with ruxolitinib for at least 24 weeks, on a stable dose for at least 4 weeks, and have ongoing splenomegaly. PROMise is split into three ruxolitinib dose categories based on platelet count which are assessed independently, Low Dose (5mg-20mg daily), Mid Dose (25mg-45mg daily) and High Dose (≥50mg daily). These are evaluated in combination with three OPN-2853 dose levels, Level 1 (20mg OD Decreased Dose), Level 2 (40mg OD Starting Dose) and Level 3 (80mg OD Increased Dose). Cohorts of patients (n=2-4) receive up to eight 21-day cycles of OPN-2853 and ruxolitinib. Patients are closely monitored for Dose Limiting Toxicities in cycle 1. The Trial Safety Committee (TSC) meets following cycle 1 to establish the dose recommendations of OPN-2853 for each dose category using the continual reassessment method (CRM). The CRM is utilised independently for each dose category, as such it is possible for the low, mid and high doses to be allocated to different OPN-2853 doses. Following cycle 8, patients may continue to receive OPN-2853 if experiencing clinical benefit and are followed up annually. Peripheral blood, bone marrow aspirate and bone marrow trephine samples are taken from all patients to measure the proportion who achieve a molecular response, and to determine the on target transcriptional response in myeloid cells. Additionally, pharmacokinetic samples are taken at specified timepoints pre and post dose to establish PK properties of OPN-2853 in combination with ruxolitinib. Current Status: To date PROMise has recruited 14 patients across all dose categories, and two TSC meetings have taken place.

Pharmacokinetics of Danofloxacin in Gushi Chickens after Single Oral and Intravenous Administration.

This study aimed to determine the pharmacokinetics of danofloxacin in Gushi chickens after a single oral (PO) and intravenous (IV) dose at 5 mg/kg body weight (BW). Thirty-two Gushi chickens, aged 20 weeks, were selected and divided into two groups at random, with each group consisting of 16 chickens, evenly distributed between males and females. Following danofloxacin administration, blood samples were taken at predetermined time intervals and the plasma was separated. The concentrations of danofloxacin in plasma were quantified by HPLC with a fluorescence detector. Then the concentrations versus time data were subjected to non-compartmental analysis (NCA) using Phoenix software (version: 8.1.0). After administering danofloxacin orally at a dose of 5 mg/kg BW to Gushi chickens, our results demonstrated that the peak concentration reached 0.53 μg/mL at 4 h. The half-life of absorption (t1/2ka) was determined to be 2.37 ± 1.60 h, and the bioavailability (F) was calculated as 40.12 ± 15.83%. For both oral and intravenous administration, the area under the concentration-time curve (AUC0-∞) was determined to be 4.72 ± 1.86 and 11.76 ± 3.25 h·µg/mL, respectively. The corresponding elimination half-life (t1/2λz) was measured as 11.24 ± 3.90 and 10.17 ± 3.72 h. Moreover, the mean residence time (MRT) was calculated as 10.20 ± 2.47 and 7.05 ± 1.97 h for these respective routes. Based on the calculated AUC/MIC ratio values, it can be inferred that the 5 mg/kg BW dosage of danofloxacin, whether administered orally or intravenously, is expected to effectively treat Escherichia coli and Pasteurella multocida infections in Gushi chickens.

Dilution of maropitant (Cerenia) in lactated Ringer solution prolongs subcutaneous drug absorption and reduces maximum plasma concentration.

The aim of this study was to determine whether the pharmacokinetics of maropitant, administered SC as a commercially available maropitant-containing injectable product (Cerenia Injectable), differ when combined with lactated Ringer solution prior to administration. We used 6 adult spayed female Beagle dogs between 3 and 6 years of age, with a mean weight of 9.58 kg. In this randomized crossover study, the dogs underwent 2 treatment protocols separated by a 14-day washout period: (1) an SC injection of 1 mg/kg of Cerenia Injectable (maropitant citrate; 10 mg/mL) and (2) 1 mg/kg of Cerenia Injectable diluted in 10 mL/kg of lactated Ringer injectable solution (LRS) given SC. Plasma maropitant concentrations were assessed by mass spectrometry. Pharmacokinetic analysis was performed using pharmacokinetic and pharmacodynamic data-analysis software to determine maximum plasma concentration (Cmax), time to reach maximum concentration, half-life, total exposure to the drug, mean residence time, clearance rate per fraction absorbed, and absorption and elimination kinetic parameters. Cmax was reduced by 26% (P = .002), the absorption rate constant decreased 80% (P = .031), and the absorption half-life increased when Cerenia was administered diluted in LRS. Administration of maropitant (Cerenia) diluted in LRS had a pharmacokinetic impact, resulting in a significantly reduced Cmax and slower absorption. Clinical efficacy was not assessed in this study.

Pharmacokinetics of a single orally administered therapeutic dosage of cyclosporine A in healthy cats

This study aimed to determine a pharmacokinetic profile for a single dosage of cyclosporine A (CsA) clinically used for immunosuppression in cats. Blood-CsA-concentrations were measured before and 1, 2, 4, 6, 8, 12 and 24 h after oral administration of 7 mg/kg body weight (BW) CsA (Atopica® oral solution) to 8 healthy adult cats using high-performance liquid chromatography coupled to mass spectrometry. Pharmacokinetic parameters were calculated using WinNonLin software based on a 1-compartment-model. The median maximum plasma-concentration of 1466 ng/ml (530–2235 ng/ml; minimum–maximum) was reached after 2.0 h (1.0–4.7 h). The area under the curve was 12,568 h x ng/ml (5732–20,820 h x ng/ml) and the apparent total clearance of the drug from plasma was 557 ml/h/kg (336–1221 ml/h/kg). Half-life of absorption into the central compartment was 0.6 h (0.4–2.6 h), half-life of elimination from the central compartment was 4.6 h (1.4–7.5 h).

Effect of a decoction of Lophira alata (Banks ex P. Gaertn) on the pharmacokinetics of risperidone: Study of a drug-herb interaction

Drug interactions may cause a drug to be more or less effective (synergism or antagonism), or cause unexpected effects on the body. Risperidone is a second-generation atypical antipsychotic medication while Lophira alata is a plant used traditionally to treat psychotic disorders. A large number of patients with psychosis have been reported to simultaneously use both orthodox and traditional medicines in Africa. This research was carried out to determine the effect of concomitant administration of risperidone and Lophira alata in healthy human volunteers. The first phase of the research was carried out to establish the baseline pharmacokinetic profile of risperidone 2 mg in 18 male subjects. The second phase was carried out after a 2-week washout period, where the subjects were randomly divided into three equal groups and group A received risperidone 2 mg and decoction of the herb (9.4mg/kg) concurrently, group B received risperidone 2 mg and decoction of the herb (9.4mg/kg) was administered after 1 hour and group C received a decoction of the herb (9.4mg/kg) and risperidone 2 mg was administered after 1 hour. Blood samples were collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after drug administration, and plasma analyses were carried out using a developed RP-HPLC method to determine the plasma concentrations. Subsequently, Kinetica 5.0 software was used to extrapolate pharmacokinetic parameters from the plasma concentrations. Results show that there was a significant (p < 0.05) increase in the rate of absorption (ka), peak plasma concentration (Cmax) and measure of drug exposed to the body (AUC0-∞) but significant (p < 0.05) decrease in the time to achieve peak plasma concentration (tmax), half-life of absorption (t1/2a) and extent of drug distribution (Vd) when risperidone and Lophira alata were administered concurrently. Drug-herb interaction was observed to be more significant (p < 0.05), when Lophira alata was administered concurrently with risperidone than when administered one hour before or after Lophira alata. Decoction of Lophira alata interacts with risperidone tablets when administered together, which may be attributed to alteration in the mechanism of risperidone absorption by Lophira alata.

Central and peripheral lung deposition of fluticasone propionate dry powder inhaler formulations in humans characterized by population pharmacokinetics.

This study aimed to gain an in-depth understanding of the pulmonary fate of three experimental fluticasone propionate (FP) dry powder inhaler formulations which differed in mass median aerodynamic diameters (MMAD; A-4.5µm, B-3.8µm and C-3.7µm; total single dose: 500µg). Systemic disposition parameter estimates were obtained from published pharmacokinetic data after intravenous dosing to improve robustness. A biphasic pulmonary absorption model, with mucociliary clearance from the slower absorption compartment, and three systemic disposition compartments was most suitable. Rapid absorption, presumably from peripheral lung, had half-lives of 6.9 to 14.6min. The peripherally deposited dose (12.6µg) was significantly smaller for formulation A-4.5µm than for the other formulations (38.7 and 39.3µg for B-3.8µm and C-3.7µm). The slow absorption half-lives ranged from 6.86 to 9.13hand were presumably associated with more central lung regions, where mucociliary clearance removed approximately half of the centrally deposited dose. Simulation-estimation studies showed that a biphasic absorption model could be reliably identified and that parameter estimates were unbiased and reasonably precise. Bioequivalence assessment of population pharmacokinetics derived central and peripheral lung doses suggested that formulation A-4.5µm lacked bioequivalence compared to the other formulations both for central and peripheral doses. In contrast, the other fomulations were bioequivalent. Overall, population pharmacokinetics holds promise to provide important insights into the pulmonary fate of inhalation drugs, which are not available from non-compartmental analysis. This supports the assessment of the pulmonary bioequivalence of fluticasone propionate inhaled formulations through pharmacokinetic approaches, and may be helpful for discussions on evaluating alternatives to clinical endpoint studies.

Intra-amniotic sildenafil administration in rabbits: Safety, pharmacokinetics, organ distribution and histologic evaluation

BackgroundThe effectiveness of sildenafil in the management of pulmonary hypertension in congenital diaphragmatic hernia (CDH) has been reported but has not been systematically evaluated. Our studies have also demonstrated that intra-amniotic (IA) sildenafil administration improves pulmonary hypertension in CDH. MethodsWe evaluated the pharmacokinetics of sildenafil after IA administration in pregnant rabbits. Following maternal laparotomy, fetuses received IA injection of 0.8 mg of sildenafil. Maternal blood, amniotic fluid, and fetal tissues were collected at various time points. The concentrations of sildenafil and its major metabolite in samples were analyzed by liquid chromatography-mass spectrometry. To assess organ toxicity, 7 days after IA sildenafil administration, fetal organs were examined histologically. ResultsAfter IA dosing, sildenafil was absorbed quickly with an absorption half-life of 0.03–0.07 h into the fetal organs. All the organs showed a maximum concentration within 1 h and the disposition half-life ranged from 0.56 to 0.73 h. Most of the sildenafil was eliminated from both mothers and fetuses within 24 h after a single dose. There was no histological evidence of organ toxicity in the fetuses after a single dose of IA administration of sildenafil. ConclusionIA sildenafil is rapidly absorbed into the fetus, distributes into the mother, and is eliminated by the mother without accumulation or fetal organ toxicity. This study confirms the feasibility and the safety of IA administration of sildenafil and enables future applications in the treatment of CDH fetuses.

The plasma and tissue kinetics of sulfadiazine and its metabolite in Ictalurus punctatus after oral gavage at two temperatures.

A plasma and tissue kinetic study of sulfadiazine (SDZ) and its metabolite, N4 -acetyl sulfadiazine (ACT-SDZ), was characterized in channel catfish (Ictalurus punctatus) following a single oral dose of 50 mg/kg at 18 and 24°C. Samples were collected at predetermined time points and determined by ultra-performance liquid chromatography. The classical one-compartmental method was used to estimate the pharmacokinetic parameters. Results showed that the changing of temperature was markedly influential on the kinetics of SDZ and ACT-SDZ in plasma and tissues. When the temperature was increased from 18 to 24°C, the elimination half-life (K10_HF) of SDZ was decreased in gill, kidney, and muscle + skin, but increased in liver and plasma. The K10_HF of ACT-SDZ also had a decreased trend in gill, liver, and plasma but had comparable values in kidney and muscle + skin. The absorption half-life (K01_HF), time to peak concentration (Tmax ), and area under concentration-time curve (AUC0-∞ ) of SDZ and ACT-SDZ all exhibited declined tendencies in plasma and tissues. The apparent volume of distribution (V_F) of SDZ in plasma was increased from 0.53 to 1.48 L/kg, and the apparent systemic total body clearance (Cl_F) was increased from 0.028 to 0.060 L/h/kg. In a word, K01_HF, Tmax , and AUC0-∞ of SDZ and ACT-SDZ were decreased in plasma and tissues with the increase of temperature, whereas the V_F and Cl_F of SDZ were increased. Meanwhile, we calculated the percentage of time profile of SDZ concentration more than minimum inhibitory concentration to total time (%T > MIC) to guide clinical usage of SDZ. When the dosage interval was 24 h, the values of %T > MIC were all >90% in plasma and most tissues. Therefore, we recommend an oral dose of SDZ at 50 mg/kg once per 24 h at 18-24°C against the fish pathogens with an MIC value of ≤6.4μg/mL.

Improving levodopa delivery: IPX203, a novel extended-release carbidopa-levodopa formulation

IntroductionIPX203 is a novel oral extended-release (ER) formulation of carbidopa (CD) and levodopa (LD) developed to address the short half-life and limited area for absorption of LD in the gastrointestinal tract. This paper presents the formulation strategy of IPX203 and its relationship to the pharmacokinetics (PK) and pharmacodynamic profile of IPX203 in Parkinson’s disease (PD) patients. MethodsIPX203 was developed with an innovative technology containing immediate-release (IR) granules and ER beads that provides rapid LD absorption to achieve desired plasma concentration and maintaining it within the therapeutic range for longer than can be achieved with current oral LD formulations. The PK and pharmacodynamics of IPX203 were compared with IR CD-LD in a Phase 2, open-label, rater-blinded, multicenter, crossover study in patients with advanced PD. ResultsPharmacokinetic data showed that on Day 15, LD concentrations were sustained above 50% of peak for 6.2 h with IPX203 vs. 3.9 h with IR CD-LD (P = 0.0002). Pharmacodynamic analysis demonstrated that mean MDS-UPDRS Part III scores prior to administration of the first daily dose were significantly lower among patients receiving IPX203 than IR CD-LD (LS mean difference –8.1 [25.0], P = 0.0255). In a study conducted in healthy volunteers, a high-fat, high-calorie meal delayed plasma LD Tmax by 2 h, and increased Cmax and AUCtau by approximately 20% compared with a fasted state. Sprinkling capsule contents on applesauce did not affect PK parameters. ConclusionThese data confirm that the unique design of IPX203 addresses some of the limitations of oral LD delivery.

Oral Pharmacokinetics of sulfadiazine and sulfamonomethoxine in female Holstein milking cows.

The efficacy of orally administered drugs in cattle is thought to be slow because of the anatomical and physiological features of their forestomach. Thus, parenteral routes are mainly preferred to administer drugs. However, the effect of some drugs with unique physicochemical properties was promptly obtained even after oral administration in clinically ill cattle. Therefore, the present study aimed to investigate pharmacokinetically the usefulness of the oral route in cattle by comparing the oral pharmacokinetic properties of two sulfonamides with different physicochemical properties. Sulfadiazine (SDZ) and sulfamonomethoxine (SMM) were administered by intravenous and oral route to four female Holstein cows with a 4-weeks washout period. Blood samples were collected over time, and SDZ and SMM concentrations in plasma were analyzed by HPLC. Data obtained from the same animal after intravenous and oral administration were simultaneously analyzed with the one compartment model, and kinetic parameters were calculated. The Tmax (mean ± SD) of SMM (2.75 ± 0.96 hr) was significantly achieved earlier than that of SDZ (5.00 ± 1.15 hr). Further, the mean absorption time of SMM (5.24 ± 0.69 hr) was significantly shorter than that of SDZ (5.92 ± 1.11 hr). Also, the half-life of absorption of SMM (3.91± 0.51 hr) was significantly shorter than that of SDZ (4.51 ± 0.82 hr). These data suggest that the absorption rates of highly unionized drugs (such as SMM) from the forestomach of cattle may be markedly higher than less unionized ones (such as SDZ).

Efficient delivery of VEGF-A mRNA for promoting diabetic wound healing via ionizable lipid nanoparticles

Diabetes is often accompanied by chronic non-healing wounds, and vascularendothelial growth factor A (VEGF-A) is crucial in the treatment of chronic diabetic wounds. However, the application of VEGF-A protein in clinic is limited due to poor absorption and short half-life of protein macromolecule. Herein, we employed an emerging protein replacement therapy by delivering VEGF-A mRNA into the body to express the desired protein to accelerate diabetic wound healing. Primarily, VEGF-A mRNA was synthesized by an in vitro transcription (IVT) method and encapsulated with an ionizable lipid-mediated nanoparticles (LNP) delivery system via a microfluidic method. The resultant LNP/VEGF-A mRNA were characterized by using dynamic light scattering (DLS) and transmission electron microscope(TEM). The nanoparticles have regular spherical morphology with an average particle size of 101.17 nm, a narrow polydispersity (PDI) of 0.17 and negative Zeta potential of −3.05 mV. The bioactivities of the nanoparticles formulation were evaluated against HUVEC cells through cell proliferation, migration and tube formation assays. It was found that the LNP/VEGF-A mRNA nanoparticles could promote endothelial cell proliferation. In addition, they exhibited successful mRNA delivery and high VEGF-A protein expression in vitro and in vivo by means of Western Blot assay and in vivo imaging system (IVIS). Finally, C57BL/6 diabetic mice model was established and intradermally treated with the LNP/VEGF-A mRNA nanoparticles. It was found that the LNP/VEGF-A mRNA treated wounds were almost healed after 14 days with an average wound area of 2.4 %, compared with the PBS group of 21.4 %. Apparently, the nanoparticles formulation was able to significantly expedite diabetic wound healing. The histological analysis containing H&E, Masson’s trichrome staining and CD31 further confirmed the healing efficacy and low toxicity of the formulation. Taken together, the LNP/VEGF-A mRNA nanoparticles can be taken up by cells to express protein effectively and improve diabetic wound healing, which might have potential application in the treatment of chronic diabetic wounds as a protein replacement therapy.